1. health and fitness
2. disease

Clinical research
European Heart Journal (2007) 28, 3012–3019
doi:10.1093/eurheartj/ehm489
Coronary heart disease
Quantitative relationship between resting heart rate
reduction and magnitude of clinical benefits in
post-myocardial infarction: a meta-regression
of randomized clinical trials
Michel Cucherat
´ de me
´decine Laennec, EA3736—Universite
´ Lyon 1, 11 rue Guillaume Paradin, 69008 Lyon France
Faculte
Received 12 June 2007; revised 13 September 2007; accepted 26 September 2007; online publish-ahead-of-print 2 November 2007
KEYWORDS
Meta-regression;
Resting heart rate reduction;
Beta-blockers;
Calcium channel blockers;
Meta-analysis;
Mortality
Introduction
Epidemiological studies suggest that lower resting heart
rate (HR) is associated with decreased cardiovascular and
all-cause mortality.1–9 HR has also been reported to be an
independent predictor of bad outcome after myocardial
infarction (MI)10,11 and a determinant of infarct size in
acute MI.12,13
A relationship between the resting HR reduction and the
mortality has also been observed in post-MI patients with
beta-blockers. In the Norwegian timolol study,13 logistic
regression analysis of the total death relative to the HR at 1
month after the start of treatment (with timolol or placebo)
remove the difference in outcome observed between the
timolol group and the placebo group. On the basis of the
results of 10 randomized controlled trials, Kjekshus14 had
observed that a correlation may exist between betablocker-induced reduction in resting HR and reduction in
total mortality. So a growing body of evidence also suggests
that pharmacological reduction in resting HR could decrease
morbidity and mortality in cardiovascular patients.10
Corresponding author. Tel: þ33 4 78 78 57 71; fax: þ33 4 78 77 69 17.
E-mail address: [email protected]
We sought to address this issue by meta-regression.
Meta-regression aims to investigate whether particular
covariates (potential effect modifier) explain any of the
difference in treatment effects between multiple studies.15
A meta-regression was performed to determine to which
extent resting HR reduction induced by the various drugs
modifying HR affects the reduction of mortality and morbidity
observed in randomized placebo-controlled trials with these
drugs in post-MI.
Methods
The meta-regression was performed according to pre-defined selection criteria for trial search and data analysis. QUOROM standards
were followed16 during all phases of the design and implementation
of this meta-regression.
Study identification
I identified relevant published and unpublished unconfounded randomized trials that compared beta-blockers and calcium blockers
with placebo in post MI. I searched electronic databases (PubMed,
Embase) from 1966 to 1 January 2006 and the Cochrane Controlled
Trials Register (CENTRAL Issue 4, 2005). The broad strategy
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2007.
For permissions please email: [email protected].
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Aims The impact on mortality outcomes of beta-blockers and calcium blockers in post-myocardial
infarction (MI) has been suggested to be related to resting heart rate (HR) reduction. A meta-regression
of randomized clinical trials was carried out to assess this relationship using weighted meta-regression
of logarithm of odds ratio against absolute HR reduction.
Methods and results Twenty-five controlled randomized trials (21 with beta-blockers and four with
calcium channel blockers) involving a total of 30 904 patients meet eligibility criteria, but only 17 documented changes in resting HR (14 with beta-blockers and three with calcium channel blockers).
A statistically significant relationship was found between resting HR reduction and the clinical benefit
including reduction in cardiac death (P , 0.001), all-cause death (P ¼ 0.008), sudden death (P ¼ 0.015),
and non-fatal MI recurrence (P ¼ 0.024). Each 10 b.p.m. reduction in the HR is estimated to reduce the
relative risk of cardiac death by 30%.
Conclusion The meta-regression of the randomized clinical trials strongly suggest that the beneficial
effect of beta-blockers and calcium channel blockers in post-MI patients is proportionally related to
resting HR reduction. Furthermore, the absence of residual heterogeneity indicated that resting HR
reduction could be a major determinant of the clinical benefit.
Relationship between resting HR and magnitude of clinical benefits
3013
described by Haynes17 was used for PubMed (search strategies are
described in the Supplementary material online).
I also reviewed the bibliographic references of the retrieved
studies, review and meta-analysis articles obtained from the
initial search. Conference proceedings of the following conferences
were hand searched: AHA, ACC, ESC from 1995 to 2005.
I also searched the WEB with the same keywords and trial registers (www.clinicaltrialresults.org and ISRCTN register).
I included trials published only in abstract form, to limit the influence of possible publication bias.
As a complementary analysis (planned in the protocol), we performed also the meta-regression using the relative risk. Publication
bias was assessed graphically using a funnel plot of the logarithm of
effect size vs. the standard error for each trial.
The meta-regression methods were implemented with the R software.22 The code was validated with running examples reported in
the methodological papers.
Statistical test were two-tailed with P , 0.05 chosen at the level
of significance.
Study selection
I assessed all potentially relevant published articles and abstracts
for inclusion. To be included, trials had to meet the following criteria: (i) randomized placebo controlled (with or without allocation
concealment); (ii) double-blind design; (iii) with ,10% attrition; (iv)
patient followed-up for 1 year or more. Trials initially planned for 1
year follow-up or more but stopped prematurely for efficacy reasons
were also considered; (v) patients with a history of MI regardless of
the period of treatment initiation. Trials with intravenous treatment
initiated during the acute phase of MI were also included; (vi) trials
had to be conducted with a beta-blocker, including those with
partial beta-1 agonist activity or with a calcium channel blocker.
Data collection and assessment of quality
Study selection
The process of study selection is outlined in Figures 1 and 2.
After selection, 21 trials with beta-blockers were included
and nine excluded, whereas four trials with calcium
channel blockers were included and 15 excluded. The
more frequent reason for exclusion was an insufficient
follow-up duration of ,1 year. (The lists of excluded trials
are given in the Supplementary material online.) Resting
HR reduction was reported in 14 of the 21 trials with betablockers and in three of the four trials with calcium
channel blockers giving a total of 17 studies applicable for
the meta-regression.
The data concerning the HR reduction being not available
for all trials, we undertook a subgroup meta-analysis to
compare trials reporting HR reduction to the others in
Statistical methods
An initial robust analysis was performed to search if a relationship
between resting HR reduction and clinical benefit exists. Clinical
benefit refers to the estimation of the treatment effect on the clinically relevant endpoints of mortality and morbidity. Odds ratio
between the active treatment and placebo group was used to estimate the clinical benefit on these endpoints. The trials were split in
three subgroups according to according to tertiles of HR reduction.
For each variable of clinical benefit, a pooled odds ratio was calculated in every subgroup of resting HR reduction using a fixed model,
given an estimate of the effect of treatment for the higher, average
and lower resting HR reductions. Then the three estimates were
compared with the x2 test for trend.19
In the second step, the analysis used a weighted meta-regression
by the inverse of variance,15,20 modelling the logarithm of odds ratio
as a linear function of the absolute resting HR reduction. In this
meta-regression, we used additive component of residual heterogeneity in order to take into account the diversity between trials
regarding drugs, regimen and patients. Restricted maximum
likelihood (REML) estimators were used.21 See online supplementary
data for model details.
Slope estimates were used to predict the relative risk reduction
potentially induced by 10 b.p.m. reduction in resting HR.
The robustness of the relationship was tested by sensitivity analyses where REML estimates were computed after exclusion of
trials with the lowest and largest resting HR reduction (one each
time). Subgroup analyses were planned to explore separately betablockers and calcium blockers.
Figure 1 Process of beta-blockers trials selection.
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All qualifying trials were assessed for adequate blinding of randomization, completeness of follow-up, and description of withdrawals using Jadad score.18
The absolute HR reduction was calculated by subtracting the
mean change from baseline observed in the placebo group from
the corresponding change observed in the active treatment group.
Changes in resting HR were determined between baseline resting
HR and resting HR after about 1 month on treatment, the exact
time of measure varying across trials. One month is the best compromise between the stabilization of the HR reduction and the
number of patients at risk and under treatment. Over this time,
occurrence of death and withdrawals decreased the number of
patients contributing towards the HR mean.
Results
3014
M. Cucherat
Effects of resting heart rate reduction
on clinical benefit
Process of calcium channel blockers trials selection.
terms of treatment effects using the relative risk and a fixed
effect model. No statistically significant heterogeneity was
found between trials reporting the HR reduction value and
those not reporting this data.
Included trials
Beta-blockers and calcium channel blockers used in analysed
trials are shown in Table 1.
Inclusion criteria of all the trials specified that enrolled
patients had definite or suspected MI. Depending of the protocol of the trial, MI was diagnosed using clinical, electrical
signs and enzyme elevation (alone or in combination). The
enzymatic definition of MI varied across time and therefore
across the trials.
Beta-blockers trials were quite well conducted with
random allocation of treatment, masking of treatment
assignment, and patient follow-up rates of .95% except
for one trial (Wilhelmsson 1974 in which 7% of patients
were lost to follow-up). However, six trials had a Jadad
score less than 4, mainly due to insufficient description of
randomization or double-blind, preventing the evaluation
of their appropriateness (allocation concealment in particular) or due to absence of withdrawals description. The
calcium channel blockers trials were also well conducted
and obtained all a Jadad score of 4 or 5.
Discussion
The present meta-regression shows a relationship between
the clinical benefit and the resting HR reduction observed
with drugs modifying HR in post-MI patients. These findings
provide firm evidence that the clinical benefit on cardiac
death, all-cause mortality, sudden death and non-fatal
recurrence of MI is proportional to the extent of resting
HR reduction.
For all these endpoints, the residual heterogeneity is estimated at zero, showing that the differences between trials
can be completely explained by resting HR reduction and
within-trial variability (sampling fluctuations). This result is
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Figure 2
According to the availability of resting HR reduction and
endpoints data, 16 trials contributed to the meta-regression
for all-cause death, 12 for cardiac death, 7 for cardiovascular death, 13 for non-fatal MI recurrence and 6 for sudden
death.
Subgroups analysis by resting HR reduction tertiles
(Table 2 and Figures 3–6) showed that larger resting HR
reduction, compared with lower resting HR reduction,
were associated with an increased mortality reduction for
cardiac death (P ¼ 0.0015), all-cause death (P ¼ 0.017)
and sudden death (P ¼ 0.005). Similar relationship was
found for non-fatal MI recurrence (P ¼ 0.033). No significant
relationship was found between resting HR reduction and
the treatment effect on cardiovascular deaths (P ¼ 0.09)
and on fatal and non-fatal MI (P ¼ 0.36). Cardiac events
were available in only three trials and did not allow any
reliable estimate of the relationship.
These results were all confirmed by the meta-regression
(Table 2 and Figures 3–6) which showed the same type of
relationship.
No residual heterogeneity was detected, except for the
cardiovascular death where a marginal heterogeneity
appeared.
In the sensitivity analysis, the results for cardiac death
remained statistically significant after the exclusion of
trials with highest or lowest resting HR reduction. For allcause mortality, sudden death, and recurrence of MI,
results remain significant after removing the trial with the
smallest resting HR reduction. Results on the same endpoints
became statistically non-significant after removing the trial
with the largest resting HR reduction but the results overall
remain qualitatively unchanged.
The meta-regression using log-relative risk (in place of log
odds ratio) led to very similar results (Table 3).
When analysis is restricted to the beta-blockers trials, a
statistically significant relationship was found between HR
reduction and log odds ratio for cardiac death (P ¼ 0.02,
meta-regression slope¼0.039), sudden death (P , 0.01)
and non-fatal MI recurrence (P , 0.01). A similar but
non-statistically significant relationship (P ¼ 0.17, metaregression slope¼0.21) was found with all-cause mortality.
Given the small number of available data (3 points),
meta-regression restricted to the calcium blocker trials
was not performed.
Funnel plots did not suggest the possibility of publication
bias.
Trial
Studied
treatment
HR at
baseline
Absolute HR
change
Age, mean
(years)
Female
(%)
B1 Andersen et al.30
B2 APSI31
B3 Aronow et al.32
B4 Australian and
Swedish Study33
B5 Baber et al.34
B6 Basu et al.35
Alprenolol
Acebutolol
Propranolol
Pindolol
NA
82.8/81.8
NA
77.9/76.8
NA
28.8
NA
25
NA
NA
81
58
NA
27
70
17
Propranolol
Carvedilol
81.3/81.9
NA
213
213.5
55
60
B7 BHAT36–38
B8 EIS39,40
B9 Hansteen et al.19
B10 Hjalmarson
et al.41
B11 Julian et al.42
B12 LIT Research
Group43
B13 Manger Cats
et al.44
B14 Multicentre
international45
B15 Norwegian
Multicentre Study
Group46
B16 Rehnqvist
et al.47
B17 Salathia et al.48
B18 Schwartz et al.
(high risk and low
risk)49
B19 Taylor et al.50
B20 Wilcox et al.51
B21 Wilhelmsson
et al.52
Calcium blockers
Propranolol
Oxprenolol
Propranolol
Metoprolol
76.2/75.7
73.5/74.2
81.5/78.7
NA
28
28
214
213
Sotalol
Metoprolol
76.4/77.3
79/79
215.8
NA
55
55
NA
40–74
(range)
55
58
Metoprolol
NA
NA
Practolol
76.8/77.2
Timolol
n (treated/
control)
Follow-up
duration (mean)
Attrition,
n (%)
Inclusion
period
Jadad’s
score
238/242
298/309
79/79
263/266
About 1 year
318 days
1 year
2 years
0
0
Unclear
Unclear
March 1976–December 1978
April 1987–September 1988
NA
February 1978–January 1980
3
5
2
4
15
23
355/365
77/74
9 months
6 months
Unclear
5 (3.31%)
1
5
36
29
31
35
1916/1921
858/883
278/282
698/697
25 months
1 year
1 year
2 yearsa
12 (0.3%)
Unclear
0
1.60%
NA
February 1992–September
1994
June 1978–October 1980
July 1979–July 1981
December 1977–July 1980
June 1981–January 1981
26
25
873/583
1195/1200
12 months
18 months
0
0.20%
January 1978–August 1980
August 1979–April 1982
4
5
NA
NA
273/280
1 year
NA
NA
3
29
55
36
1533/1520
3.40%
NA
5
74.4/74.3
218
61
38
945/939
12 months, up to 24
months
17 months
Unclear
January 1978–October 1979
4
Metoprolol
NA
NA
NA
NA
154/147
36 months
NA
NA
2
Metoprolol
Oxprenolol
NA
NA
NA
NA
NA
NA
46
NA
416/384
485/488
1 year
22 months (at least
6 months)
0.50%
NA
NA
NA
5
4
Oxprenolol
Propranolol
Alprenolol
76/77
79.5/80
NA
26
217
26
51
NA
NA
NA
28
NA
632/471
259/129
114/116
48 months
1 year
2 years
Unclear
0
(16) 7%
1973
NA
January 68–
4
5
3
C1 MDPIT et al.53
Diltiazem
71/72
23
48
20
1234/1232
3.20%
February 1983–June 1986
5
C2 CRIS54
C3 DAVIT II55
C4 SPRINT I56
Verapamil SR
Verapamil
Nifedipine
73/74
75/75
76.9/77.4
22
26
NA
55
NA
58
9
20
15
531/542
878/897
1130/1146
25 months (at least
12 months)
23.5 months
16 months
1 year
5 (0.47%)
NA
NA
1985–87
February 1985–
August 1981–July 1983
5
4
4
Beta-blockers
In the Go
¨teborg Metoprolol Study (B10), the double blind and placebo-controlled study lasted for 3 months. After that all patients were given open treatment with metoprolol and outcome was reported after 2 years.
3015
a
5
4
5
5
Relationship between resting HR and magnitude of clinical benefits
Table 1 Characteristics of the trials included in the meta-regression
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3016
M. Cucherat
Table 2 Result summary of the analysis by subgroup and meta-regression
Endpoint
Number of
trials with
sufficient
data
Subgroup
analysis by HR
reduction
tertile, P-value
for trend
Meta-regression
slope
Meta-regression,
P-value for slope
Residual
heterogeneity
Per cent reduction
in odds ratio for 10
and 15 b.p.m.
reduction in
resting HRa
All-cause death
Cardiac death
Cardiovascular deathd
Sudden death
Non-fatal MI recurrence
Fatal and non-fatal MI
Cardiac event (fatal and
non-fatal)
16
12
7
6
12
6
3
0.017
0.002
0.090
0.005
0.033
0.360
—
20.0249
20.0396
20.0204
20.0531
20.0243
0.00227
0.008b
,0.001c
0.550
0.015b
0.024b
0.960
—
0
0
0.0891
0
0
—
—
22/31
33/45
—
41/55
22/31
—
—
a
Per cent reduction in odds ratio are obtained by the exponential of the meta-regression slope.
Robustness result remains statistically significant only after removal of the lowest HR reduction. The removal of the largest HR implies a NS result.
Robustness result remains statistically significant after removal of the trial with the largest HR reduction or those with the smallest.
d
Cardiovascular deaths add to cardiac deaths vascular deaths and strokes.
b
c
Figure 4 By tertiles subgroup analysis and meta-regression for cardiac death. Odds ratios represented are comparing odds between the active treatment and
placebo group.
compatible with the assumption that the resting HR reduction
explains all the benefit of these drugs. From this
meta-regression, there is no evidence of a drug/class specific
part in the benefit. The lack of mortality reduction observed
with calcium antagonists could be totally explained by the
absence of resting HR reduction with the tested drugs
without need to take into account a specificity of the
calcium blockers. After adjustment on resting HR reduction,
there is no residual heterogeneity to be explained by other
factors between the trials. Thus, resting HR reduction
appears to be the major determinant of the clinical benefit
induced by the drugs modifying resting HR in post MI patients.
For cardiovascular deaths, no statistically significant
relationship was found most probably due to the small
number of trials available for this endpoint, seven in place of
12 for cardiac deaths. The value of the slope for this endpoint
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Figure 3 By tertiles subgroup analysis and meta-regression for all-cause death. Odds ratios represented are comparing odds between the active treatment and
placebo group.
Relationship between resting HR and magnitude of clinical benefits
3017
Figure 5 By tertiles subgroup analysis and meta-regression for sudden death. Odds ratios represented are comparing odds between the active treatment and
placebo group. There were no data available for sudden death in the calcium blockers trials.
Table 3 Comparison of the results given by the meta-regression with the odds ratio and the relative risk
Endpoint
All-cause death
Cardiac death
Cardiovascular death
Sudden death
Non-fatal MI recurrence
Fatal and non-fatal MI
Cardiac event (fatal and non-fatal)
Subgroup analysis by HR
reduction tertile, P-value
for trend
Meta-regression, P-value for
slope
Per cent reduction for
10 b.p.m. reduction in HR
Odds ratio
Relative risk
Odds ratio
Relative risk
Odds ratio
Relative risk
0.017
0.002
0.090
0.005
0.033
0.360
—
0.015
0.002
0.110
0.005
0.030
0.320
—
0.008
,0.001
0.550
0.015
0.024
0.960
—
0.008
,0.001
0.570
0.016
0.020
0.990
—
21
33
—
41
22
—
—
20
30
—
39
21
—
—
20.0204 is similar to the one observed with the cardiac deaths
20.0396. Moreover, the relationship could have been weakened by the adding of the vascular deaths (including among
others fatal stroke) not influenced by the HR.
The meta-regression was undertaken using the odds ratio
for statistical reasons. The odds ratio has symmetric properties that the relative risk does not have; therefore, odds
ratio is more appropriate to use for a meta-regression than
the relative risk. However, in practice, it appears that the
relative risk is more relevant for clinicians (among others)
than odds ratio.23,24 The analyses carried out on relative
risk gave consistent results with analyses performed on
odds ratio. For the sake of simplicity, the relative risk can
be used to report the findings for this meta-regression.
Our results are consistent with those obtained by
Kjekshus14,25 in 1986 (updated in 1999) when considering
only beta-blockers. Our results are not simply the replication of these previous ones, given that five additional betablocker trials were added and that the focus was widened to
the other drugs modifying HR.
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Figure 6 By tertiles subgroup analysis and meta-regression for non-fatal myocardial infarction recurrence. Odds ratios represented are comparing odds between
the active treatment and placebo group.
3018
Supplementary material
Supplementary material is available at European Heart
Journal online.
Acknowledgement
We thank D. Lebrasseur, I.R.I.S and the scientific documentation
department of I.R.I.S. for their help in bibliographic searching.
Conflict of interest: M.C. has received research support from and is
a consultant to Servier.
Funding
This study was supported by an unrestricted grant from Servier, Inc.
The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or in the writing of the
report.
References
1. Benetos A, Rudnichi A, Thomas F, Safar M, Guize L. Influence of heart rate
on mortality in a French population: role of age, gender, and blood
pressure. Hypertension 1999;33:44–52.
2. Dyer AR, Persky V, Stamler J, Paul O, Shekelle RB, Berkson DM, Lepper M,
Schoenberger JA, Lindberg HA. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol 1980;112:736–749.
3. Gillum RF, Makuc DM, Feldman JJ. Pulse rate, coronary heart disease, and
death: the NHANES I Epidemiologic Follow-up Study. Am Heart J 1991;
121:172–177.
4. Greenland P, Daviglus ML, Dyer AR, Liu K, Huang CF, Goldberger JJ,
Stamler J. Resting heart rate is a risk factor for cardiovascular and noncardiovascular mortality: the Chicago Heart Association Detection
Project in Industry. Am J Epidemiol 1999;149:853–862.
5. Kannel WB, Kannel C, Paffenbarger RS Jr, Cupples LA. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J 1987;113:
1489–1494.
6. Mensink GB, Hoffmeister H. The relationship between resting heart rate
and all-cause, cardiovascular and cancer mortality. Eur Heart J 1997;18:
1404–1410.
7. Palatini P, Casiglia E, Julius S, Pessina AC. High heart rate: a risk factor for
cardiovascular death in elderly men. Arch Intern Med 1999;159:585–592.
8. Seccareccia F, Pannozzo F, Dima F, Minoprio A, Menditto A, Lo Noce C,
Giampaoli S. Heart rate as a predictor of mortality: the MATISS project.
Am J Public Health 2001;91:1258–1263.
9. Shaper AG, Wannamethee G, Macfarlane PW, Walker M. Heart rate,
ischaemic heart disease, and sudden cardiac death in middle-aged
British men. Br Heart J 1993;70:49–55.
10. Hjalmarson A. Significance of reduction in heart rate in cardiovascular
disease. Clin Cardiol 1998;21:II3–II7.
11. Hjalmarson A, Gilpin EA, Kjekshus J, Schieman G, Nicod P, Henning H,
Ross J Jr. Influence of heart rate on mortality after acute myocardial
infarction. Am J Cardiol 1990;65:547–553.
12. Stangeland L, Grong K, Vik-Mo H, Andersen KS, Lekven J. Is reduced
cardiac performance the only mechanism for myocardial infarct size
reduction during beta adrenergic blockade? Cardiovasc Res 1986;20:
322–330.
13. Gundersen T, Grottum P, Pedersen T, Kjekshus JK. Effect of timolol on
mortality and reinfarction after acute myocardial infarction: prognostic
importance of heart rate at rest. Am J Cardiol 1986;58:20–24.
14. Kjekshus JK. Importance of heart rate in determining beta-blocker efficacy in acute and long-term acute myocardial infarction intervention
trials. Am J Cardiol 1986;57:43F–49F.
15. van Houwelingen HC, Arends LR, Stijnen T. Advanced methods in
meta-analysis: multivariate approach and meta-regression. Stat Med
2002;21:589–624.
16. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the
quality of reports of meta-analyses of randomised controlled trials: the
QUOROM statement. Quality of reporting of meta-analyses. Lancet
1999;354:1896–1900.
Downloaded from by guest on October 21, 2014
In previous meta-analyses, only the intrinsic sympathomimetic activity has been identified as a potential effect modifier of the beta-blockers benefit26,27 and could be, thereby, a
confounding factor for the relation between resting HR
reduction and benefit. However, a main consequence of the
intrinsic sympathomimetic activity is a low reduction in
resting HR. In fact, the relation between resting HR reduction
and benefit could explain the trend towards a decreased
benefit with drugs with intrinsic sympathomimetic activity.
Some potential limitations must be discussed. Data dredging is the main pitfall in reaching reliable conclusion from
meta-regression.28 Here, it can be discarded because the
covariate was pre-specified. Clearly, this work is hypothesis
testing and not exploratory like an intensive search among a
large collection of candidate covariables would be.
These results are quite robust. The relationship is found
with robust subgroup analysis that did not require strong
statistical assumptions. Moreover, the validity of these
observations is strengthened by the robustness of the sensitivity analyses and by the very good fitting with the absence
of residual heterogeneity.
The relationship with resting HR lowering may be potentially confounded by other trials, drugs, or patients characteristics. Given the relatively small number of trials
reporting resting HR reduction, multivariate analyses are
not feasible in this analysis based on summary data for
each considered trials. Blood pressure reduction is a candidate confounding factor as it is probable that blood pressure
lowering induced by these drugs is in part correlated with
the induced resting HR reduction. Despite that statistical
adjustment was not feasible, it is improbable that the
found relationships were confounded by blood pressure
change. In randomized trials, clinical benefit of blood
pressure lowering needed several years to appear and mortality reductions were smaller than those observed in the
present post-MI trials.29 Moreover, in the trials used in this
meta-regression, patients were included irrespective to
the presence of a hypertension.
The between trial heterogeneity concerning drugs and
patients is taken into account with the use of a random
effect model. The absence of heterogeneity does not
resolve by itself the confounding concern but gives some
reassurance that the extent of resting HR lowering is a
strong marker of clinical benefit in the trials.
An interesting result of this meta-regression is the absence
of residual heterogeneity that could be interpreted as all the
benefit is brought by resting HR reduction without any other
mechanism. This attractive interpretation is limited as it
derives from non-statistically significant results. However, it
is at least reasonable to conclude that the available data
do not permit to exclude that the HR reduction is the
major determinant of the benefit of drugs like beta-blockers
or calcium blockers in post-MI.
In conclusion, in post-MI condition, this meta-regression of
randomized clinical trials robustly suggests that the benefit
of drugs modifying HR is strongly related to the magnitude of
reduction in resting HR. This implies that whatever the
mechanism leading to the decrease in resting HR, a same
reduction could result in the same morbidity and mortality
reduction. Each 10 b.p.m. reduction in resting HR is estimated to reduce the relative risk of cardiac death by
about 30%, the risk of sudden death by 39%, leading to a
reduction in the relative risk of all-cause mortality of 20%.
M. Cucherat
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17. Haynes RB, McKibbon KA, Wilczynski NL, Walter SD, Werre SR. Optimal
search strategies for retrieving scientifically strong studies of treatment
from Medline: analytical survey. BMJ 2005;330:1179.
18. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ,
McQuay HJ. Assessing the quality of reports of randomized clinical trials:
is blinding necessary? Control Clin Trials 1996;17:1–12.
19. Hansteen V, Moinichen E, Lorentsen E, Andersen A, Strom O, Soiland K,
Dyrbekk D, Refsum AM, Tromsdal A, Knudsen K, Eika C, Bakken J Jr,
Smith P, Hoff PI. One year’s treatment with propranolol after myocardial
infarction: preliminary report of Norwegian multicentre trial. Br Med J
(Clin Res Ed) 1982;284:155–160.
20. Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted? Stat Med 2002;21:1559–1573.
21. Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a
comparison of methods. Stat Med 1999;18:2693–2708.
22. R Development Core Team. R: A Language and Environment for Statistical Computing [Program]. Vienna, Austria: R Foundation for Statistical
Computing; 2006.
23. Deeks J. When can odds ratios mislead? Odds ratios should be used only in
case-control studies and logistic regression analyses. BMJ 1998;317:
1155–1156. author reply 1156–1157.
24. Sackett DL, Deeks JJ, Altman DG. Down with odds ratios!. Evidence-Based
Med 1996;1:164–166.
25. Kjekshus J, Gullestad L. Heart rate as therapeutic target in heart failure.
Eur Heart J 1999;1:H64–H69.
26. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and
after myocardial infarction: an overview of the randomized trials. Prog
Cardiovasc Dis 1985;27:335–371.
27. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta blockade
after myocardial infarction: systematic review and meta regression
analysis. BMJ 1999;318:1730–1737.
28. Higgins JP, Thompson SG. Controlling the risk of spurious findings from
meta-regression. Stat Med 2004;23:1663–1682.
29. Turnbull F. Effects of different blood-pressure-lowering regimens on
major cardiovascular events: results of prospectively-designed overviews
of randomised trials. Lancet 2003;362:1527–1535.
30. Andersen MP, Bechsgaard P, Frederiksen J, Hansen DA, Jurgensen HJ,
Nielsen B, Pedersen F, Pedersen-Bjergaard O, Rasmussen SL. Effect of
alprenolol on mortality among patients with definite or suspected
acute myocardial infarction. Preliminary results. Lancet 1979;2:865–868.
31. Boissel JP, Leizorovicz A, Picolet H, Ducruet T. Efficacy of acebutolol after
acute myocardial infarction (the APSI trial). The APSI Investigators. Am J
Cardiol 1990;66:24C–31C.
32. Aronow WS, Ahn C, Kronzon I. Effect of propranolol versus no propranolol
on total mortality plus nonfatal myocardial infarction in older patients
with prior myocardial infarction, congestive heart failure, and left ventricular ejection fraction .or¼40% treated with diuretics plus angiotensin-converting enzyme inhibitors. Am J Cardiol 1997;80:207–209.
33. The effect of pindolol on the two years mortality after complicated myocardial infarction. Eur Heart J 1983;4:367–375.
34. Baber NS, Evans DW, Howitt G, Thomas M, Wilson T, Lewis JA, Dawes PM,
Handler K, Tuson R. Multicentre post-infarction trial of propranolol in 49
hospitals in the United Kingdom, Italy, and Yugoslavia. Br Heart J 1980;
44:96–100.
35. Basu S, Senior R, Raval U, van der Does R, Bruckner T, Lahiri A. Beneficial
effects of intravenous and oral carvedilol treatment in acute myocardial
infarction. A placebo-controlled, randomized trial. Circulation 1997;96:
183–191.
36. Lampert R, Ickovics JR, Viscoli CJ, Horwitz RI, Lee FA. Effects of propranolol on recovery of heart rate variability following acute myocardial
infarction and relation to outcome in the Beta-Blocker Heart Attack
Trial. Am J Cardiol 2003;91:137–142.
37. A randomized trial of propranolol in patients with acute myocardial
infarction. II. Morbidity results. JAMA 1983;250:2814–2819.
38. A randomized trial of propranolol in patients with acute myocardial
infarction. I. Mortality results. JAMA 1982;247:1707–1714.
39. European Infarction Study (EIS). A secondary prevention study with slow
release oxprenolol after myocardial infarction: morbidity and mortality.
Eur Heart J 1984;5:189–202.
40. Bethge KP, Andresen D, Boissel JP, von Leitner ER, Peyrieux JC,
Schroder R, Tietze U. Effect of oxprenolol on ventricular arrhythmias:
the European Infarction Study experience. J Am Coll Cardiol 1985;6:
963–972.
41. Hjalmarson A, Elmfeldt D, Herlitz J, Holmberg S, Malek I, Nyberg G,
Ryden L, Swedberg K, Vedin A, Waagstein F, Waldenstrom A,
Waldenstrom J, Wedel H, Wilhelmsen L, Wilhelmsson C. Effect on mortality of metoprolol in acute myocardial infarction. A double-blind randomised trial. Lancet 1981;2:823–827.
42. Julian DG, Prescott RJ, Jackson FS, Szekely P. Controlled trial of sotalol
for one year after myocardial infarction. Lancet 1982;1:1142–1147.
43. Lopressor Intervention Trial Research Group. The Lopressor Intervention
Trial: multicentre study of metoprolol in survivors of acute myocardial
infarction. Eur Heart J 1987;8:1056–1064.
44. Cats Manger V, van Capelle FJL, Lie KI, Durrer Dnregist. Effect of treatment with 2 100 mg metoprolol on mortality in a single-center study
with low placebo mortality rate after infarction. Circulation 1983;
68(Suppl. 3):181.
45. Improvement in prognosis of myocardial infarction by long-term
beta-adrenoreceptor blockade using practolol. A multicentre international study. Br Med J 1975;3:735–740.
46. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981;304:801–807.
47. Rehnqvist N, Olsson G. Influence on ventricular arrhythmias by chronic
post infarction treatment with metoprolol. Circulation 1983;68(Suppl.
3):69.
48. Salathia KS, Barber JM, McIlmoyle EL, Nicholas J, Evans AE, Elwood JH,
Cran G, Shanks RG, Boyle DM. Very early intervention with metoprolol
in suspected acute myocardial infarction. Eur Heart J 1985;6:190–198.
49. Schwartz PJ, Motolese M, Pollavini G, Lotto A, Ruberti U, Trazzi R. Prevention of sudden cardiac death after a first myocardial infarction by
pharmacologic or surgical antiadrenergic interventions. J Cardiovasc
Electrophysiol 1992;3:2–16.
50. Taylor SH, Silke B, Ebbutt A, Sutton GC, Prout BJ, Burley DM. A long-term
prevention study with oxprenolol in coronary heart disease. N Engl J Med
1982;307:1293–1301.
51. Wilcox RG, Roland JM, Banks DC, Hampton JR, Mitchell JR. Randomised
trial comparing propranolol with atenolol in immediate treatment of suspected myocardial infarction. Br Med J 1980;280:885–888.
52. Wilhelmsson C, Vedin JA, Wilhelmsen L, Tibblin G, Werko L. Reduction of
sudden deaths after myocardial infarction by treatment with alprenolol.
Preliminary results. Lancet 1974;2:1157–1160.
53. The Multicenter Diltiazem Postinfarction Trial Research Group. The effect
of diltiazem on mortality reinfarction after myocardial infarction. N Engl
J Med 1988;319:385–392.
54. Rengo F, Carbonin P, Pahor M, DeCaprio L, Bernabei R, Ferrara N,
Carosella L, Acanfora D, Parlati S, Vitale D. A controlled trial of verapamil
in patients after acute myocardial infarction: results of the calcium
antagonist reinfarction Italian study (CRIS). Am J Cardiol 1996;77:
365–369.
55. Effect of verapamil on mortality major events after acute myocardial
infarction (the Danish Verapamil Infarction Trial II—DAVIT II). Am J
Cardiol 1990;66:779–785.
56. Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT). A
randomized intervention trial of nifedipine in patients with acute myocardial infarction. The Israeli Sprint Study Group. Eur Heart J 1988;9:
354–364.
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Relationship between resting HR and magnitude of clinical benefits